The long range objective of this line of study is to provide a better understanding of the role of the vascular endothelium and lipoproteins in the genesis of atherosclerosis. Heightened endothelial permeability is an important factor for atherosclerotic plaque development. This hyperpermeable state is likely a consequence of endothelial dysfunction. Lipoproteins, especially high low density lipoprotein (LDL) levels, have been identified through epidemiologic studies to be associated with the premature development of atherosclerosis. There is some evidence indicating that exposure to high LDL concentrations promotes endothelial dysfunction. We have recently demonstrated in vitro an increase in endothelial endocytosis with prolonged exposure to atherogenic levels of LDL. Such a cellular functional change is likely an important feature of lipoprotein- induced endothelial dysfunction. The specific focus of this proposal is to characterize and determine the physiologic mechanism(s) for lipoprotein- mediated alterations in endothelial endocytosis. A major aspect of these studies will be to examine the contribution of cytoskeletal configuration changes, oxygen free radical generation, arachidonic acid metabolites, calcium fluxes, and pH changes toward lipoprotein-induced increases in endothelial cells exposed to high lipoprotein concentrations for prolonged periods. The lipoproteins to be examined include LDL, very low density lipoprotein (VLDL), and high density lipoprotein (HDL). Results from these studies will provide new insights into important physiologic mechanisms for lipoprotein-induced hyperpermeability.